PROJECT SUMMARY/ABSTRACT: FirstString Research has identified a novel peptide that shows therapeutic potential in the treatment of age- related macular degeneration (AMD). This Phase I SBIR will assess both the feasibility and mechanism of action involved in the topical delivery of a synthetic connexin-based peptide, aCT1, for the treatment of AMD. AMD is a retinal disease in patients who progressively lose their central vision through pathological and damaging conditions of the macula and the development of VEGF-mediated choroidal neovascularization (CNV). Approved therapeutics that target VEGF are the therapeutic option of choice but are costly, require chronic highly invasive intravitreal injections, have safety concerns and are modestly effective. An effective, safe, topical formulation for the treatment of AMD represents a significant and much needed innovation. aCT1 is a small, soluble peptide based on the C-terminal sequence of connexin43, engineered to directly translocate into cells without the requirement of any potentially toxic compound for topical or intracellular drug delivery. When applied topically on skin wounds aCT1 safely promotes healing, reduces inflammation and scarring, and promotes complex tissue regeneration. aCT1 peptide's unique properties in skin wound healing and tissue regeneration combined with evidence that the non-vascular components of AMD correspond to a submacular wound healing or tissue repair response suggest therapeutic opportunity in the treatment of AMD. Preliminary studies show that topical application of an aCT1 eyedrop formulation reduces CNV and stabilizes the barrier function of the retinal pigment epithelium (RPE) in mouse models mimicking the pathophysiology AMD. The goal of this proposal is to evaluate the therapeutic potential and mechanism of action of the aCT1 peptide in an eye drop formulation, as a novel minimally invasive therapy, to prevent the progression of AMD and restore retinal function. To accomplish this goal, FirstString Research will: 1.) Further delineate aCT1's therapeutic potential and mechanism of action in preserving RPE barrier function and inhibiting CNV using mouse models of AMD; where aCT1 might reduce inflammation by reducing Cx43 hemichannel activity and stabilize tight junction integrity. Experiments will include the investigation of potential synergy between aCT1 and anti-VEGF therapeutics. 2.) Identify the dose in which aCT1 can be delivered by eye-drops to achieve efficacy in a rabbit model of CNV and examine potential side effects in uninjured eyes. The completion of these aims will provide sufficient data to demonstrate therapeutic potential and mechanism of action of aCT1 in stabilizing the RPE network in order to support formulation optimization and further validation in additional large animal efficacy and PK/toxicity studies in a Phase 2 proposal.